Abstract Obesity represents a burgeoning health threat that predispose millions of people to reduced life expectancy; additionally, obese people incur $2741 higher annual healthcare costs than normal-weight individuals. Unfortunately, few effective medical options exist for the prevention or treatment of obesity. To design effective treatments, we must understand the mechanisms that mediate energy homeostasis. Leptin and its receptor (LepRb) play crucial roles in the control of energy balance. Understanding the molecular and neural mechanisms of leptin action represents the long-term goal of our previous and proposed studies under this project (DK056731). Our findings to date have revealed the importance of STAT3 and a second, pY-independent, LepRb signal for leptin action; have determined the transcriptional targets (potential downstream mediators) of leptin; and have identified crucial neuronal mediators of leptin action. We propose to understand the molecular and neural mechanisms of leptin action by: 1: Testing the hypothesis that specific genes regulated by leptin in LepRb neurons play crucial roles in leptin action and the control of energy balance. 2: Testing the hypothesis that the deletion of specific pY-independent regions of LepRb will alter the leptin-mediated control of neuronal function and energy balance, despite intact STAT3 signaling. 3: Testing the hypothesis that distinct subpopulations of hypothalamic LepRb neurons control POMC and AgRP neurons to modulate energy homeostasis. Overall, these studies will define the molecular and neural mechanisms by which leptin controls energy balance. These pathways may be dysregulated in disease and may represent targets for therapeutic intervention.